Parenteral nutrition (PN), also known as parenteral hyperalimentation, is a medical treatment that supplies nutrition-maintaining compositions intravenously, and is indicated for a variety of mammalian disorders, such as cancer, gastrointestinal diseases, major body burns, extensive wounds, and AIDS. Partial parenteral nutrition supplies only part of daily nutritional requirements, supplementing oral intake. Many hospitalized patients receive dextrose or amino acid solutions by this method. Total parenteral nutrition treatment (TPN) supplies all daily nutritional requirements intravenously, circumventing the gut. TPN may be employed following surgery, when feeding by mouth or using the gut is not possible, when a patient's digestive system cannot absorb nutrients due to chronic disease, or, if nutrition cannot be met by enteral feeding and supplementation. Premature and sick infants often require extended periods of TPN.
Compositions for parenteral nutrition generally contain at least water, glucose, amino acids, and optionally emulsified fats. They may be aseptically compounded from amino acid solutions, dextrose solutions, and/or lipid emulsions. PN compositions may further contain vitamins, electrolytes and essential trace elements.
PN compositions generally contain only negligible amounts of iron. Because of concerns about incompatibility and toxicity, iron is not routinely added to PN admixtures.
Patients who require TPN may develop iron deficient anemia despite administration of hematopoietic nutrients (e.g., folate, vitamin B12, pyridoxine, ascorbic acid, copper, zinc, and amino acids). Iron deficiency is a primary cause of anemia in patients receiving TPN and reflects a patient's inability to compensate for blood losses associated with underlying disease, multiple surgeries, or frequent phlebotomies.
Iron deficiency is corrected by the administration of iron-containing compounds. In general, healthy subjects who suffer from iron deficiency ingest oral preparations containing iron salts as a safe, cheap and effective means of replenishing iron stores. Patients, however, are frequently non-compliant with oral iron supplements due to associated gastrointestinal side-effects, e.g., nausea, vomiting, bloating, discomfort, indigestion, heartburn, and constipation. In patients receiving TPN, administration of oral iron may not be feasible either because the mechanical factors that preclude use of enteral nutrition also preclude the use of oral and/or enteral iron, or patients may not be able to absorb oral iron, such as patients with malabsorption syndrome. Furthermore, oral iron administration is commonly associated with unpleasant and/or deleterious gastrointestinal side effects thereby resulting in poor compliance.
Various forms of iron have been suggested for intravenous administration, including, by way of example, low molecular weight ferrous iron compounds, such as ferrous citrate or ferrous gluconate, and iron bound to polymeric materials, such as iron dextran and iron saccharates. Formulations containing simple iron salts, such as iron chloride, sulfate or ascorbate, are considered too toxic for parenteral administration, since transfer of these iron salts to the patient's blood liberates free iron, i.e., iron that is not bound to a natural or synthetic ligand, such as transferrin, or ferritin. Free iron, whether in its +2 (ferrous) or +3 (ferric) oxidation state, is a transition element capable of catalyzing free radical generation and lipid peroxidation. The ferrous (Fe(II)) ion is reactive, and by a series of cyclic redox reactions, leads to the production of highly reactive hydroxyl radicals by the Fenton reaction, or alkoxyl and peroxyl radicals from the breakdown of lipid peroxides. Likewise, the highly charged ferric (Fe(III)) aquo ion will tend to precipitate at physiological pH due to hydrolysis reactions to form insoluble hydroxides, and its interactions with plasma proteins may result in their denaturation and partial precipitation. All of these actions are toxicities with serious adverse effects and have prevented clinical use of conventional ferrous or ferric iron salts in formulations that are administered intravenously.
Colloidal iron compounds that are iron-carbohydrate complexes are currently formulated for parenteral administration of iron. In the United States, colloidal iron compounds approved by the U.S. Food and Drug Administration for i.v. administration include iron dextran (INFeD®, Watson Pharma, Inc.; Dexferrum®, American Regent, Inc.), iron gluconate (Ferrlecit®, Watson Pharma, Inc.), or iron sucrose (Venofer®, American Regent, Inc.). Intravenous administration of colloidal iron compounds such as these is known to cause serious adverse effects, including pain, severe and/or life-threatening anaphylactoid reactions, organ toxicity, release of catalytically active iron that is associated with higher risk of or exacerbation of infection and possibly cancer, and oxidative stress and chronic inflammation that is causatively associated with atherosclerosis, coronary artery disease, and strokes (Physicians' Desk Reference, 58th Ed., pages 568-570, 3319-3322 (2004)). Furthermore, parenteral formulations containing conventional colloidal iron preparations have potent, but highly variable, cytotoxic potentials (Zager et al., 2004, Kidney Intl. 66: 144-156). Zager et al. concluded that parenteral formulations of colloidal iron complexes have potent cytotoxic potentials that can be exhibited at clinically relevant iron concentrations. The persistence of polymeric iron complexes in the circulation for several days following i.v. infusion may allow uptake by microorganisms and thereby promote microbial growth. Recent studies have also shown that i.v. administration of colloidal iron compounds may be associated with an increased morbidity and mortality from infections (Collins et al., 1998, J. Am. Soc. Nephrol. 9: 205A). Therefore, the use of i.v. colloidal iron requires close monitoring for adverse patient responses with each administration.
It has been proposed that maintenance parenteral nutrition patients receive intravenous polymeric iron supplements. A prospective study to evaluate the intravenous iron dextran (Imferon®, Merrill National Laboratories, Cincinnati, Ohio, US) dosage needed to restore serum iron levels in patients receiving TPN showed that 87.5-175 mg/week iron effectively raised serum iron levels over a 3 week period (Norton et al, 1983, Journal of Parenteral and Enteral Nutrition 7:457-461). For ease of administration polymeric iron dextran has been administered as an additive to parenteral nutrition mixtures (Porter et al, 1988, Journal of American College of Nutrition 7(2): 107-110).
The compatibility of iron with parenteral nutrition admixtures, however, has not been clearly established. One study has shown 1-day compatibility of ferrous citrate, a monomeric ferrous salt, with a single parenteral nutrition component, amino acid solution (Sayers et al., 1983, J. Parenter. Enteral Nutr. 7(2): 117-120). A second study has shown compatibility of iron dextran with amino acid-dextrose parenteral admixtures (Wan et. al., 1980, Am. J. Hosp. Pharm. 37: 206-210.) In contrast, several studies found that iron dextran added to TPN formulation caused breakdown of the admixture, coalescence of lipid droplets, and cracking and creaming of the lipid component (Driscoll et al., 1995, Am. J. Health-Syst. Pharm. 52:623-634; Vaughan et al., 1990, Am. J. Hosp. Pharm. 47:1745-1748). The effect of colloidal iron dextran on the stability of parenteral nutritional (PN) emulsions has been analyzed (Driscoll et al., 1995, supra). Driscoll et al. (1995, supra) determined that the trivalent cation content derived from colloidal iron dextran was the only variable that affected the stability of nutritional emulsions, accounting for approximately 60% of a potentially dangerous increase in fat particle sizes observed. In addition, a percentage of large fat particles (i.e., fat particles greater than 5 μm in diameter; PFAT5) that was greater than 0.4% was observed to be associated with unstable PN emulsions and disruption of their integrity.
Product labeling for each of the conventional colloidal iron-containing formulations warns specifically that the formulation is not to be added to parenteral nutrition solutions for intravenous administration (Physicians' Desk Reference, 58th Ed., pages 568-570, 3319-3322 (2004)). There is also concern that prolonged iron administration in parenteral nutrition may have undesirable adverse effects. Iron overload has been reported in children receiving prolonged iron supplementation in TPN (Ben Hariz et al., 1993, J Pediatr. 123: 238-241)
Consequently, there is a need for an alternative and more physiologic method of administering bioavailable iron intravenously as a component of a parenteral nutrition composition. The present invention addresses that need.